Biomedical subjects

M Penalver

Publications and source records attributed to M Penalver.

At least 37 records · Page 2Linked to original sources

PubMed1993

National survey of ovarian carcinoma. Part V. The impact of physician's specialty on patients' survival.

BACKGROUND: Data analysis of the recent National Survey of Ovarian Carcinoma revealed significant differences in patterns of care among various physician specialists. The goal of this study was to determine if different care patterns led to differences in patient survival. METHODS: Data were collected from 25 consecutive patients with ovarian cancer diagnosed in 1983 and 1988 from 1230 hospitals with cancer programs across the United States. RESULTS: A total of 12,316 patients from 904 hospitals were registered, of whom 20.8% were cared for by gynecologic oncologists (GYO), 45.0% by obstetrician-gynecologists (OBG), and 21.1% by general surgeons (GS). GYO preferred the upper-lower midline incision in 44.1% of patients, whereas both OBG and GS chose the low midline approach in 44-45%. GYO performed more hysterectomies, oophorectomies, omentectomies, and lymph node and peritoneal biopsies than did other specialists. Although the rates of surgery of the small intestine were comparable between GYO and GS, the latter performed significantly more colostomies and resections of the large intestine. The optimal debulking rates were: GYO, 42-45%; OBG, 40-44%; and GS 25%. There was no significant survival difference between patients cared for by GYO and those cared for by OBG for all stage divisions. However, with the exception of patients with Stage I disease, patients cared for by GS had significantly reduced survival than did those cared for by GYO and OBG (P < 0.004). CONCLUSION: Efforts must be made to ensure that more patients with ovarian cancer are cared for by physicians in the appropriate specialties.

Female↗

PubMed1993

National survey of ovarian carcinoma. VI. Critical assessment of current International Federation of Gynecology and Obstetrics staging system.

BACKGROUND: The Commission on Cancer of the American College of Surgeons recently completed a national survey of patients with ovarian cancer. From the large database, the prognostic value of current International Federation of Gynecology and Obstetrics (FIGO) staging system for ovarian carcinoma was re-examined. METHODS: Data was collected from 25 consecutive ovarian carcinomas diagnosed in 1983 and 1988 at 904 hospitals with cancer programs. Among a total of 12,316 cases, 5156 patients had long-term survival data. RESULTS: The overall 5-year survivals were 88.9 +/- 0.9%; 57.1 +/- 2.4%; 23.8 +/- 1.3%; and 11.6 +/- 0.9% for Stages I, II, III, and IV, respectively. Pairwise survival comparisons using Lee-Desu statistic confirmed the prognostic value of current staging system (P < 0.00001). When survival data was substratified further to substage division, the 5-year survivals were: IA, 92.1 +/- 0.9%; IB, 84.9 +/- 3.4%; IC, 82.4 +/- 2.0%; IIA, 69.0 +/- 4.3%; IIB, 56.4 +/- 3.6%; IIC, 51.4 +/- 4.5%; IIIA, 39.3 +/- 2.8%; IIIB, 25.5 +/- 2.6%; IIIC, 17.1 +/- 1.4%; and IV, 11.6 +/- 0.9%. As the disease process becomes more advanced, patients' survival reduces proportionally. However, the survival reduction is relatively small between IB-IC and IIB-IIC divisions. Survival comparisons revealed significant prognostic value for most substage divisions (P = 0.03-0.0002) except for IB-IC and IIB-IIC combinations (P > 0.33). Further analyses revealed no significant differences between IB-IC and IIB-IIC patients in several prognostic parameters such as age, histologic grade, cell type, and amount of residual disease. CONCLUSIONS: These data support the current FIGO staging system. However, Substages IB-IC and IIB-IIC should be combined to respective single substages.

Adult↗

PubMed1993

Chemosensitivity testing in ovarian cancer.

Most patients with ovarian cancer currently are treated primarily with surgery and chemotherapy. Drug selection usually is not based on individualized in vitro sensitivity studies but on reported response rates of clinical trials. Attempts to include in vitro chemosensitivity testing into the management of ovarian cancer have been disappointing to clinicians. Tumor cells from fresh human ovarian cancer do not grow well under artificial in vitro growth conditions. The selection of cells that happen to proliferate in vitro (e.g., human tumor clonogenic assay) has resulted in low plating efficiencies (0.001-0.1% of plated cells). The vigorous mechanical and enzymatic tumor disaggregation, done to obtain a single-cell suspension, further reduces the number of cells that grow in vitro, resulting in low overall evaluability rates of 40-70% for the human tumor clonogenic assay. At the University of Miami, a new in vitro chemosensitivity assay was developed that detected the decrease in total tumor cell viability by measuring intracellular adenosine triphosphate as a function of in vitro drug response. Preliminary data on 31 tumor tissues from patients, which was evaluated with this method, showed a sensitivity of 92% and a specificity of 100%. Since these initial studies, data were gathered on more than 150 fresh gynecologic tumor specimens to evaluate single drugs and drug combinations at five concentrations (range, 10-500% of reported peak plasma concentrations). The evaluability rate for ovarian tumors was more than 90%. Some tumors showed almost complete cell kill at the lowest drug concentration; others had only a limited response at the highest level. Drug-response patterns also were variable for combined drug exposure. These findings underscore the heterogeneity of drug response in morphologically similar tumors and the importance of characterizing individual chemosensitivity profiles for patients before drug treatment.

Drug Screening Assays, Antitumor↗

PubMed1993

Preliminary experience with a modified Tenckhoff catheter for intraperitoneal chemotherapy.

This study reports our preliminary experience with a modified Tenckhoff catheter for intraperitoneal chemotherapy, primarily designed to be larger, longer, and have more perfusion holes. There were 137 catheters implanted in 125 ovarian cancer patients from June 1988 to December 1990, among which 116 were actually used for intraperitoneal chemotherapy. A total of 559 cycles of intraperitoneal chemotherapy was given with a range of 1 to 16 uses per catheter. There were seven infections (6.0%), four inflow obstructions (3.4%), three bowel perforations (2.6%), and one leakage (0.8%). Among patients with catheter infection, three had delayed bowel perforation. Although the incidence of inflow obstruction was reduced from 5.5 to 3.4%, the improvement did not reach statistical significance. The frequency of delayed bowel perforation and infection were similar to the literature experience of other catheters. An unused catheter should be removed to avoid this serious complication. Further study is needed to evaluate fully the performance of this catheter system.

Antineoplastic Agents↗

PubMed1993

Radiosensitization of uterine cancer cell lines by cytotoxic agents.

Radiotherapy remains an integral part of uterine cancer therapy. Overcoming radioresistant tumors by sensitizers continues to be a prime objective in radiotherapy research. In this study, the effects of five cytotoxic agents on two radiosensitive and four radioresistant uterine cancer cell lines were investigated. The ATP bioluminescence was used to measure surviving fractions. Data analysis was done using the linear quadratic model and radiosensitivity index D. Both AN3 and SKUT1B were radiosensitive with Ds of 1.73 and 1.72 Gy, respectively. The resistant cell lines had the following D values: AE7, 3.50; ECC, 6.61; HEC1A, 4.59; and HEC1B, 13.49 Gy. The average radiosensitization effects for various drugs were measured by reduction of D: DXR 45 +/- 7, DDP 40 +/- 9, 5FU 55 +/- 10, MITO 59 +/- 14, and HU 1.7 +/- 7%. Except for HU, Wilcoxon analyses revealed that these sensitizing effects were significant with P < 0.02. In summary, Adriamycin, 5-fluorouracil, cisplatin, and mitomycin-C have the potential to be radiosensitizers in uterine cancer cell lines.

Adenosine Triphosphate↗

PubMed1993

The role of DNA index as a prognostic factor in early cervical carcinoma.

The value of DNA index as a prognostic factor in early cervical cancers was investigated. A total of 124 patients who underwent radical hysterectomy for stages IB-IA cervical cancers from 1/1982 to 12/1985 were included. Paraffin blocks were available in only 98 patients for the analysis. After dewaxing, rehydrating, and enzyme disaggregation, cells were subjected to dual parameter flow cytometry. Tumor DNA index was calculated and the results were correlated with 5-year survival, stage, grade, tumor size, nodal metastasis, surgical margins, and lymphovascular invasion. There were 1% hypoploid, 7.3% diploid, 72.9% aneuploid, 16.7% tetraploid, and 2.1% hyperploid. At the end of 5 years, there were 69 alive and 27 dead patients with mean DNA indices of 1.50 +/- 0.3 and 1.70 +/- 0.3, respectively. t Test analysis revealed that mean DNA index of deceased patients was significantly higher than that of alive ones (P = 0.008). Survival analysis demonstrated the prognostic significance of DNA index 1.70 (P = 0.017). Median survival of patients with DNA index of 1.70 or greater was 36 months in contrast to 73.5 months for those with DNA index less than 1.70. Multivariate analysis subsequently confirmed DNA index of 1.70 as an independent prognostic indicator with a hazard ratio of 2.05.

Carcinoma↗

PubMed1993

Adenosquamous carcinoma of the cervix: prognosis in early stage disease treated by radical hysterectomy.

The prognosis of adenosquamous carcinoma of the cervix compared to the pure cell types of this disease is a controversial issue. Survival rates vary widely among published series, with some authors finding the prognosis to be much worse and others finding it to be equal. We have studied a group of 290 patients, all of whom had the diagnosis of stage IB or IIA cervical cancer, and all of whom were treated by radical hysterectomy and bilateral pelvic and paraaortic lymphadenectomy. The pathology specimens were reviewed for every case. Median follow-up for all living patients was 73 months. Forty-five patients (15.5%) had adenosquamous histology, 220 (75.9%) had squamous cell, and 25 (8.6%) had adenocarcinoma. By X2, there was no significant difference among the three groups with regard to race, economic status, number of grade 3 lesions, number with positive pelvic lymph nodes, number with positive margins, stage distribution (IB vs IIA), or number of recurrences. Using Student's t test, there was no significant difference between any combination of two groups with regard to mean patient age, mean depth of invasion, or mean tumor size. Estimated disease-free survival and overall survival were not different among the three cell types. We conclude that for early stage cervical cancer treated by radical hysterectomy, the adenosquamous cell type does not carry a worse prognosis than either of the pure cell types.

Adenocarcinoma↗

PubMed1993

Cell cycle perturbations of platinum derivatives on two ovarian cancer cell lines.

Cisplatin continues to be one of the most commonly used cytotoxic agent. Problems of drug resistance and nephrotoxicity have generated interest in new platinum derivatives. In this study, we used flow cytometry to study their effects on cell kinetics and to see if the extent of cell cycle perturbations can be used to determine relative potency. The following four platinum derivatives were tested: cisplatin, carboplatin, 254S, and NK121 on two human ovarian cancer cell lines: BG1 and CAOV3. Flow cytometric analysis revealed a dynamic spectrum of cell kinetic perturbations, which included sequential S-G2 block, concomitant S-G2 block, and a dominant S block with abolition of G2 block. Platinum derivatives NK121, 254S, and CARBO induced an average of 54.5 +/- 5.6, 21.2 +/- 5.5, and 2.5 +/- 2.8% more S-G2 blocks than cisplatin, respectively. When comparing the severity of S-G2 blocks and requiring a p-value of 0.05, the order of increasing potency was: cisplatin, carboplatin, 254S, and NK121.

Carboplatin↗

PubMed1992

In vitro evaluation of a novel chemotherapeutic agent, Adozelesin, in gynecologic-cancer cell lines.

Adozelesin is a derivative of an extremely cytotoxic compound, CC1065. This entirely new class of drug binds preferentially to DNA and facilitates alkylation reaction. In the present study, we used the adenosine triphosphate (ATP) chemosensitivity assay to compare the cytotoxic potency of Adozelesin with that of common chemotherapeutic agents in ten gynecologic-cancer cell lines. Flow cytometry was also used to study its effects on cell-cycle kinetics. The mean drug concentrations required to produce a 50% reduction in ATP levels as compared with controls [IC50] were: Adriamycin, 0.17 +/- 0.06 microM; 4OH-Cytoxan, 18 +/- 3 microM; cisplatin, 17 +/- 7 microM; 5-fluorouracil, 183 +/- 116 microM; and Adozelesin, 11.0 +/- 5.4 pM. Thus, Adozelesin was 10(4) - 10(7) times more potent than Adriamycin, cisplatin, 5-fluorouracil, and Cytoxan. Cell kinetics studies revealed significant S and G2 blocks such as those previously reported for other alkylating agents.

Adenocarcinoma↗

PubMed1992

Infectious complications after gastrointestinal surgery in patients with ovarian carcinoma and malignant ascites.

One hundred four patients with ovarian cancer underwent intestinal reconstruction as part of a cytoreductive effort or for relief of intestinal obstruction from July 1980 to June 1990. Twenty-four percent of patients were obstructed preoperatively, while the remaining seventy-six percent had bowel resections performed in concert with a debulking procedure. The overall infectious complication rate was 14.4%. No statistical association was found between the presence of ascites at the time of laparotomy and infectious morbidity (P = 0.58). The use of a preoperative mechanical bowel preparation was associated with a significant reduction in infectious morbidity (P = 0.01). Additionally, patients considered in adequate nutritional condition experienced significantly less infectious complications than those patients in poor nutritional condition (P = 0.03). Intestinal procedures involving the large bowel were marginally associated with increased infectious complications (P = 0.13). Neither preoperative radiotherapy, the presence of preoperative obstruction, disease presence, extent of debulking, number of intestinal procedures, or hand versus stapled anastomosis was found to be significantly associated with infectious complications. It is concluded that the presence of ascites does not increase the infectious complication rate in ovarian cancer patients who undergo small or large bowel reconstructive procedures. Additionally, patients with preoperative bowel obstruction or previous abdominal radiation therapy were not found to experience a significant increase in the infectious complication rate in the current series.

Anti-Bacterial Agents↗

PubMed1992

Determination of hormonal response in uterine cancer cell lines by the ATP bioluminescence assay and flow cytometry.

Although progesterone receptor status has been shown to correlate with response to hormonal therapy, not all progesterone receptor-positive patients respond to this treatment and additional biologic assays are needed to help better predict clinical response to hormonal therapy. This study explored the potential of the ATP bioluminescence assay and flow cytometry as biological assays of hormonal response. Five uterine cancer cell lines were used: AE7, ECC-1, HEC1A, AN3, and SKUT1B. Cells were exposed to Provera or tamoxifen at 0.1, 0.2, 0.5, 1, 2, and 5X (X equal to peak plasma concentrations: 1.0 micrograms/ml Provera and 0.1 micrograms/ml tamoxifen). For correlation, estrogen and progesterone receptors were determined by the standard dextran-coated charcoal method. Only AE7 and ECC-1 were positive for progesterone receptors (501 fmol/mg AE7, 194 fmol/mg ECC-1) and the rest were negative (less than 8 fmol/mg). Tamoxifen exerted no inhibition to the above cell lines. Meanwhile, Provera exerted dose-response inhibition on both AE7 and ECC-1 cell lines. The effects of accumulation of G0-G1 phase and reduction of S, G2 cells (P less than 0.05), but not on the HEC1A cell line (P = 0.4). These changes confirmed the antiproliferative property of Provera. Further studies are needed to establish the role of the ATP bioluminescence assay and flow cytometry as biological assays of hormonal response.

Adenocarcinoma↗

PubMed1992

The use of ATP bioluminescence assay and flow cytometry in predicting radiosensitivity of uterine cancer cell lines: correlation of radiotoxicity and cell cycle kinetics.

Radiotherapy remains an important part of uterine cancer treatment. This study was designed to evaluate the potential of the ATP bioluminescence assay and flow cytometry for predicting radiosensitivity. Correlation of these two modalities revealed important insights into the relationship of radiotoxicity and cell kinetic effects. Six human uterine cancer cell lines were used: AE7, ECC1, HEC1A, HEC1B, AN3, and SKUT1B. Doses of cobalt 60 were 0, 1, 2, 5, 8, and 10 Gy. The ATP bioluminescence assays were performed on Day 7. Cell samples were taken at 0, 24, 48, 72, 96, and 168 hr for flow cytometry. The linear-quadratic model was used to fit survival data and mean inactivation dose D was calculated. Among parameters such as D, alpha and beta coefficients, and surviving fraction at 2 Gy (SF2), both D and SF2 correlated best with survival data. Radiation effects on the cell cycle did not correlate with D and revealed two distinct patterns: either a G1 accumulation with mild G2 block or a G1 depletion and severe G2 block. The S cells consistently demonstrated a biphasic pattern with an initial reduction followed by an accumulation. In summary, the ATP assay was shown to have potential in the study of radiosensitivity. Radiation-induced cell kinetics appeared to vary with intrinsic cellular differences and, thus, could not be used to predict radiosensitivity.

Adenosine Triphosphate↗

PubMed1992

Comparative evaluation of pirarubicin and adriamycin in gynecologic cancer cell lines.

Pirarubicin (PIRA) has been shown to have improved potency with less cardiac toxicity in several phase I and II clinical trials in Japan and Europe. Since Adriamycin (DXR) remains one of the most potent drugs in treatment of gynecologic cancers, this derivative has the potential to become an important chemotherapeutic agent. In this study, we compared the performance of these two drugs against a panel of 10 gynecologic cancer cell lines. The ATP chemosensitivity assays were used to determine dose-response curves. Flow cytometry was used to study cell kinetic response to both drugs. Using an IC50 value of 0.2 micrograms/ml as a cutoff for drug sensitivity, 4 cell lines, ECC1, HEC1B, BG1, and SKOV3, were considered resistant to DXR. By comparing IC50s, PIRA was 3.4 +/- 0.4 times more potent than DXR (P = 0.05). The other 6 cell lines, AN3, AE7, HEC1A, CAOV3, SKUT1B, and ME180, were considered sensitive to DXR. In this group of cell lines, PIRA was 1.6 +/- 0.3 times more potent than DXR (P = 0.5). Both PIRA and DXR elicited a spectrum of cell kinetics. By comparing the magnitude of G2 blocks at 0.1 micrograms/ml, PIRA was approximately 2-5 times more potent than DXR in SKUT1B, HEC1A, and BG1 cell lines. PIRA also displayed a reverse dose-response pattern of G2 block so that at high dose, cell cycle kinetics would mirror those of untreated controls. This observation supports the presence of a resistant tumor subpopulation and the concept of tumor heterogeneity.

Antibiotics, Antineoplastic↗

PubMed1992

The use of ATP bioluminescence assays in selecting a drug screen panel for chemosensitivity testing of uterine cancer cell lines.

The ATP bioluminescence assay has demonstrated a strong potential to become a clinical assay for chemosensitivity testing. Currently, chemotherapy of gynecologic cancers remains controversial and empirical. To optimize the patient's chance of survival and to justify related toxicities, the chemoregimen should be individualized and based on the patient's chemosensitivity profiles. This study was performed to identify a panel of active drugs against uterine cancer cell lines for possible use in future chemosensitivity testing. We used the ATP chemosensitivity assays to screen 12 common cytotoxic agents against six uterine cancer cell lines. Drug concentrations required for a 50% surviving fraction were defined as IC50s. When using an IC50 of 0.21 PPC (peak plasma concentration) as a cutoff value for sensitivity, the following 8 drugs were considered effective for uterine cancer cell lines: actinomycin D, Adriamycin, vinblastine, etoposide, 5-fluorouracil, methotrexate, cytosine arabinoside, and mitomycin-C. Meanwhile, 4 drugs, cisplatin, 4OH-Cytoxan, bleomycin, and Alkeran with mean IC50s of 2.1 +/- 0.7, 0.8 +/- 0.1, greater than 5.0, and 0.75 +/- 0.36 PPC, respectively, were considered inactive or partially active with higher IC50s than peak plasma concentrations. In conclusion, the above panel of promising drugs can be further tested in animal models or human cancer specimens for possible use in chemosensitivity testing of uterine cancer patients.

Adenocarcinoma↗

PubMed1991

The effects of Provera on chemotherapy of uterine cancer cell lines.

Even though progestin is commonly added to many chemotherapy regimens in the treatment of uterine cancers, its role is still unproven. Since progestin is antiproliferative, its tendency to arrest cells in G1 phase may interfere with cytotoxic mechanisms. The ATP chemosensitivity assay and flow cytometry were used to study the effects of a progestational compound such as Provera on three single agents and four drug combinations. Uterine cancer cell lines included progesterone-receptor (PR)-positive AE7 and ECC1 and PR-negative HEC1A, HEC1B, AN3, and SKUT1B. Provera selectively affected only PR-positive cell lines. It imposed an antiproliferative effect on drug-induced cell-cycle perturbations by reducing G2 and S blocks and minimizing G1 depletion. When using IC50s (concentrations required for 50% growth inhibition) of 0.5 as a cutoff for drug sensitivity and resistance, Provera significantly improved the IC50s of the drug-resistant subgroup from 1.95 +/- 0.36 to 0.71 +/- 0.19 (P = 0.009) but not those of the drug-sensitive subgroup (P = 0.13). In summary, Provera appeared to work independently from cytotoxic mechanisms. Its improvement of cytotoxicity was most pronounced in resistant cell lines bearing progesterone receptors.

Antineoplastic Agents↗

PubMed1991

Comparative evaluation of single and combination chemotherapy in uterine cancer cell lines.

Controversy over the chemotherapy of uterine cancers still exists. This study was designed to directly compare the efficacy of various chemotherapy combinations, CAP (Cytoxan, Adriamycin, cisplatin), CAF (Cytoxan, Adriamycin, 5-fluorouracil), MF (melphalan, 5-fluorouracil), CP (Cytoxan, cisplatin), to single agents, Adriamycin (DXR), Cytoxan (CYT), cisplatin (DDP), and carboplatin (CARBO). Five human endometrial cell lines and one sarcoma cell line were used: AE7, ECC-1, HEC1A, HEC1B, AN3, and SKUT1B. The ATP chemosensitivity assay was used to determine dose-response curves of various treatments. By using mean IC50's for comparison, CAF and MF were twice as effective in cell kill as CAP (P = 0.01, 0.03, respectively). There was however no significant difference between CAF, MF, and DXR (P = 0.12, 0.46, 0.34). When dose comparison is used, combinations CAP, CAF, and MF appeared to be 3 to 15 times more potent than DDP, CYT, or CARBO. In summary, Adriamycin remained the most effective single drug for uterine cancer cell lines. Its cytotoxicity was equivalent to that of combinations CAP, CAF, and MF.

Antineoplastic Agents↗

PubMed1990

Stage III and stage IV endometrial carcinoma: a review of 41 cases.

Forty-one patients with clinical stage III and IV carcinoma of the endometrium presented to Jackson Memorial Hospital between the years 1977 and 1988. These patients were studied as to their presenting symptoms, prognostic factors, therapeutic regimens, and survival. Sixty-one percent of our patients presented with postmenopausal bleeding. Prognostic factors included extent of disease and tumor bulk rather than histologic type, grade, or depth of myometrial invasion. Overall 5-year survival was 7/32 (22%), with 6/22 (27%) for stage III and 1/10 (10%) for stage IV. Those patients who received surgery plus radiation fared better than those who received either alone. Hormonal therapy offered little, if any, benefit. CAP-M chemotherapy was used as adjunctive treatment in 10 patients and its use is discussed. It is our hope that we may later use this study to compare the newer surgical staging in advanced cases of endometrial carcinoma with the previously used clinical staging system.

Adenocarcinoma↗

PubMed1990

Chemical enhancement of cisplatin cytotoxicity in a human ovarian and cervical cancer cell line.

While many advances have been made in the chemotherapy of gynecologic cancers, treatment failures remain a major clinical problem. A growing understanding of the mechanisms of tumor cell resistance to antineoplastic drugs provides a framework for the development of chemotherapy regimens containing agents capable of modulating tumor response. Using a short-term ATP bioluminescence assay we studied the ability of two methylxanthines (caffeine, pentoxifylline) and an inhibitor of ADP-ribosyl transferase (3-aminobenzamide) to enhance cisplatin cytotoxicity in gynecologic cancer cell lines. Our findings of significantly enhanced cisplatin-induced cytotoxicity with two different analysis techniques confirms the effectiveness of these agents. These results may have future clinical significance.

Adenosine Triphosphate↗